Incidence of and risk factors for kidney dysfunction in childhood cancer survivors

Incidence of and risk factors for kidney dysfunction in childhood cancer survivors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Incidence of and risk factors for kidney dysfunction in childhood cancer survivors Wataru Shimabukuro, Satoru Hamada, Hideki Sakiyama, Shinobu Kiyuna, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6761059/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Oct, 2025 Read the published version in Pediatric Nephrology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Although therapeutic advances have improved the life expectancy of children with cancer, the late complication of kidney dysfunction represents a challenge. We aimed to measure the cumulative incidence and identify risk factors for kidney dysfunction (eGFR 5 years. The cumulative incidence of kidney dysfunction was measured and risk factors were identified using the Kaplan–Meier method, the log-rank test, and Cox proportional hazards analysis. Results Eighty-four survivors, who were a median of 5.7 years old at the start of treatment, were studied for a median of 9.0 years. Nineteen, 12, 15, 4, 20, 14, and 34 patients were treated using cisplatin (CDDP), carboplatin, ifosfamide, nephrectomy, total-body irradiation, kidney irradiation (≥ 10 Gy), or hematopoietic stem cell transplantation, respectively; and 14 developed relapse/secondary cancer. During treatment, acute kidney injury developed in 57.5% of patients. The cumulative incidence of kidney dysfunction was 10.7% after 5 years and 21.8% after 10 years. The log-rank test identified older age (≥ 5 years) at the initiation of treatment, solid tumor, CDDP therapy, ifosfamide therapy, and nephrectomy as significant risk factors; and a Cox proportional hazards model showed that older age (HR 3.89, p = 0.033), CDDP therapy (HR 8.80, p < 0.001), and nephrectomy (HR 10.20, p = 0.016) were significant risk factors. Conclusions The long-term monitoring of kidney function is important for survivors of childhood cancer who received their initial treatment when relatively old, underwent CDDP-based chemotherapy, or underwent nephrectomy. Childhood cancer survivor Kidney dysfunction Late complication Chronic kidney disease Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Therapeutic advances have improved the life expectancy of children with cancer. In Europe, the 5-year survival rate for such patients increased from 44% (95% CI: 44–45%) in the 1970s to 77.9% (95% CI: 77.4–78.3%) in 2000–2007 [ 1 , 2 ]. In Japan, the incidence of cancer-related mortality significantly decreased by 3.8% per year ( p < 0.05) between 1980 and 2003 for boys and 3.6% per year ( p < 0.05) between 1980 and 2001 for girls [ 3 ]. However, as the life expectancy of children with cancer continues to improve, late complications affecting various organs, including the kidneys, are increasingly prevalent [ 4 ]. Few studies have focused on the cumulative incidence of kidney dysfunction or on the risk factors for kidney dysfunction in survivors of childhood cancer, and very few studies are aimed at identifying risk factors for kidney dysfunction using multivariate analysis. Therefore, the purpose of the present study was to measure the cumulative incidence of and identify risk factors for kidney dysfunction in survivors of childhood cancer. Methods Study sample We identified 175 children with cancer who were ≤ 15 years old, underwent their initial treatment after 2000, visited the University of the Ryukyus Hospital between January 2021 and June 2024, and survived for > 5 years. Those with chromosomal or genetic abnormalities (one had 21 trisomy and another had Noonon syndrome) were excluded, as were those who did not undergo whole-body chemotherapy (six with Langerhans cell histiocytosis and four with chronic myeloid leukemia). Data collection The following clinical information was collected from the medical records of the patients: age at the initiation of treatment, the length of the observation period after the initial treatment, sex, diagnosis, underlying condition, treatment details (the use of anticancer drugs, including cisplatin [CDDP], carboplatin [CBDCA], and ifosfamide [IFO]); nephrectomy; local radiation therapy; hematopoietic stem cell transplantation (HSCT); total-body irradiation (TBI) followed by HSCT; kidney radiation dose; relapse or development of secondary cancers; mortality; serum creatinine (Cr) concentration; development of acute kidney injury (AKI) during treatment; development of kidney dysfunction; introduction of continuous kidney replacement therapy; and blood pressure, serum phosphorus concentration, and proteinuria > 5 years after the initial treatment. Definition of kidney dysfunction Kidney dysfunction was defined using a serum Cr-based estimated glomerular filtration rate (Cr-eGFR) < 90 mL/min/1.73 m 2 . The serum Cr concentration was measured using an enzymatic assay on a JCA-BM 6070 G (JEOL, Tokyo, Japan). Cr-eGFR was calculated using an equation based on the serum Cr concentrations of Japanese children for patients aged ≤ 18 years 0 months [ 5 ] and an equation based on the serum Cr concentrations of Japanese adults for patients aged ≥ 18 years 1 month [ 6 ]. Definition of AKI A diagnosis of AKI can be made according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Acute Kidney Injury, using an increase in serum Cr of ≥ 0.3 mg/dL within 48 hours, an increase in serum Cr to ≥ 1.5 times the baseline value (known or presumed to have occurred within the previous 7 days), or a urine volume < 0.5 mL/kg/hour for 6 hours [ 7 ]. However, because detailed urine output data were not recorded, AKI was diagnosed purely on the basis of the serum Cr concentration in the present study. Exposure assessment Information regarding chemotherapy was obtained from the patients’ medical records. The nephrotoxic agents used included CDDP, CBDCA, and IFO. For each agent, the cumulative dose (mg/m 2 ) was calculated. Exposure to abdominal or whole-body radiation was assessed using the radiation therapy summaries, and the kidney radiation exposure was estimated by reviewing the treatment fields and calculating the radiation dose. Because doses of radiation delivered to the kidneys of ≥ 10 Gy have been reported to be a risk factor for kidney dysfunction [ 8 ], the dose of radiation delivered to the kidneys was categorized as ≥ 10 Gy or < 10 Gy. Surgical interventions involving the kidney, such as nephrectomy, were identified from the surgical records. Statistical analysis The cumulative incidence of kidney dysfunction was evaluated using the Kaplan–Meier method. The log-rank test and Cox proportional hazards analysis were performed to evaluate the relationship between kidney dysfunction and various factors, including age at the initiation of treatment; sex; tumor type (solid or hematologic); the use of CDDP therapy, CBDCA therapy, IFO therapy, or TBI; kidney radiation dose, the use of HSCT, the occurrence of relapse or secondary cancers, and the development of AKI. Treatments administered after the onset of kidney dysfunction were not included in the multivariate analysis. In addition, a Cox proportional hazards model was used to identify risk factors for kidney dysfunction. The data generated were non-normally distributed continuous data and are expressed as median and interquartile range. p < 0.05 was considered to represent statistical significance. The data were analyzed using JMP Pro version 17.2.0 (SAS Institute Japan, Tokyo, Japan). Results Data from 84 survivors, including 34 girls (40.5%), 52 with blood cancers (61.9%), and 32 with solid tumors (38.1%), were analyzed (Table 1 , Supplemental Table 1). The details of the treatments are shown in Supplementary Table 2. In the entire cohort of survivors, the median (IQR) age of the patients at the initiation of treatment and the duration of the observation period were 5.7 years (1.7–10.2 years) and 9.0 years (6.9–11.8 years), respectively. Nineteen, 12, 15, 4, 20, 14, and 34 of the patients were treated using CDDP, CBDCA, IFO, nephrectomy, TBI followed by HSCT, a kidney radiation dose ≥ 10 Gy, and HSCT, respectively. Twelve and two of the patients relapsed or developed secondary cancer, respectively, and three died. During the treatment period, 46 of 80 patients (57.5%) developed AKI (data were not available for four patients). Table 1 Patients’ characteristics Characteristic All patients (n = 84) Blood cancer (n = 52) Solid tumor (n = 32) Age at initial treatment, median (interquartile range) 5.7 (1.7–10.2) years 7.1 (2.8–10.7) years 2.3 (0.9–9.1) years Observation period, median (interquartile range) 9.0 (6.9–11.8) years 9.1 (7.2–11.8) years 8.8 (6.1–11.6) years Sex Female Male 34(40.5%) 50(59.5%) 19(36.5%) 33(63.5%) 15(46.9%) 17(53.1%) Treatment a Cisplatin Carboplatin Ifosfamide Nephrectomy Total-body irradiation Kidney radiation dose ≥ 10 Gy Hematopoietic stem cell transplantation 19(22.6%) 12(14.3%) 15(17.9%) 4(4.8%) 20(23.8%) 14(16.7%) 34(40.5%) 1(1.9%) 2(3.8%) 5(9.6%) 0(0.0%) 15(28.8%) 8(15.4%) 22(42.3%) 18(56.3%) 10(31.3%) 10(31.3%) 4(12.5%) 5(15.6%) 6(18.8%) 12(37.5%) Relapse 12(14.3%) 9(17.3%) 3(9.4%) Secondary cancer 2(2.4%) 1(1.9%) 1(3.1%) Mortality 3(3.6%) 2(3.8%) 1(3.1%) AKI during treatment b Stage 1 Stage 2 Stage 3 18/80(22.5%) 18/80(22.5%) 10/80(12.5%) 12/49(24.5%) 10/49(20.4%) 10/49(20.4%) 6/31(19.4%) 8/31(25.8%) 0/31(0.0%) eGFR (mL/min/1.73 m 2 ) at the final visit 60–89 30–59 ≤ 29 16(19.0%) 4(4.8%) 0(0.0%) 8(15.4%) 0(0.0%) 0(0.0%) 8(25.0%) 4(12.5%) 0(0.0%) Continuous kidney replacement therapy 0(0.0%) 0(0.0%) 0(0.0%) Hypertension at the final measurement c 9/81(11.1%) 6/51(11.88%) 3/30(10.0%) Hypophosphatemia at the final examination d 11/74(14.9%) 5/47(10.6%) 6/27(22.2%) Proteinuria at the final examination e 3/75(4.0%) 0/46(0.0%) 3/29(10.3%) a Excluding treatment after the onset of kidney dysfunction. b Four patients had not received an initial treatment at our hospital and no laboratory data were available. c Patients who did not have their blood pressure, serum phosphorus concentration, or urine analyzed once ≥ 5 years after their initial treatment were excluded. AKI acute kidney injury, eGFR estimated glomerular filtration rate. Kidney dysfunction was diagnosed in 20 of the patients (23.8%) at their last visits, and there were 5-year and 10-year cumulative incidences of 10.7% and 21.8%, respectively, according to the Kaplan–Meier curve (Fig. 1 ). None of the patients initiated continuous kidney replacement therapy during the study. The patients were divided into older and younger age groups at the initiation of treatment using a threshold of 5 years, based on ROC analysis (Fig. 2 ). The log-rank test identified risk factors for kidney dysfunction of older age ( p = 0.007), the presence of a solid tumor ( p = 0.005), the use of CDDP therapy ( p < 0.001), the use of IFO therapy ( p = 0.001), and nephrectomy ( p = 0.028) (Fig. 3 ). Subgroup analyses were then performed with respect to CDDP and IFO therapy, with the patients being divided into dosage-based groups (Fig. 4 ) [ 9 , 10 ]. Log-rank analysis of the use of CDDP therapy using three groups (≥ 500 mg/m 2 , < 500 mg/m 2 , and none) showed no significant difference between the ≥ 500 mg/m 2 and < 500 mg/m 2 groups ( p = 0.069); and log-rank analysis of the use of IFO therapy using three groups (≥ 45 g/m 2 , < 45 g/m 2 , and none) showed no significant difference between the ≥ 45 g/m 2 and < 45 g/m 2 groups ( p = 0.854). In addition, log-rank analysis of four groups of patients (CDDP + IFO therapy, CDDP therapy only, IFO therapy only, and none) showed no significant difference between the CDDP therapy only and CDDP + IFO therapy groups ( p = 0.061). Cox proportional hazards analysis was then performed. Univariate analysis showed that older age (HR 4.04, p = 0.013), the presence of a solid tumor (HR 3.39, p = 0.008), the use of CDDP therapy (HR 5.84, p < 0.001), the use of IFO therapy (HR 4.31, p = 0.003), and nephrectomy (HR 4.55, p = 0.046) were risk factors for kidney dysfunction. Multivariate analysis that included these five factors showed that older age (HR 3.89, p = 0.033), the use of CDDP therapy (HR 8.80, p < 0.001), and nephrectomy (HR 10.20, p = 0.016) were significant risk factors (Table 2 ). Table 2 Results of the Cox proportional hazards analyses to identify factors influencing the development of kidney dysfunction Univariate analysis Multivariate analysis Variable HR 95% CI p HR 95% CI p Age at initial treatment ≥ 5 years ( vs . < 5 years) 4.04 1.35–12.11 0.013 3.89 1.12–13.52 0.033 Male ( vs . female) 1.76 0.68–4.60 0.245 Solid tumor ( vs . blood cancer) 3.39 1.38–8.34 0.008 0.82 0.24–2.78 0.752 CDDP ( vs . no use) 5.84 2.41–14.15 < 0.001 8.80 2.51–30.80 < 0.001 CBDCA ( vs . no use) 1.35 0.39–4.66 0.639 IFO ( vs . no use) 4.31 1.63–11.35 0.003 2.28 0.69–7.54 0.178 Nephrectomy ( vs . no nephrectomy) 4.55 1.03–20.22 0.046 10.20 1.56–66.89 0.016 TBI ( vs . no TBI) 1.17 0.45–3.07 0.745 Kidney radiation dose ≥ 10 Gy ( vs . <10 Gy) 1.44 0.52–3.98 0.480 HSCT ( vs . no HSCT) 1.73 0.71–4.21 0.223 Relapse/SC ( vs . no Relapse/SC) 1.12 0.38–3.36 0.834 AKI 1.28 0.50–3.24 0.606 HR hazard ratio, CDDP cisplatin, CBDCA carboplatin, IFO ifosfamide, TBI total-body irradiation, HSCT hematopoietic stem cell transplantation, SC secondary cancer, AKI acute kidney injury. Discussion In the present study, we analyzed a cohort of survivors of childhood cancer whose kidney function was monitored for the ≥ 5 years following their initial treatment. When kidney function is evaluated during treatment, it is important to consider the effects of AKI and that the Cr-eGFR can be overestimated in the presence of muscle weakness. Therefore, we considered that chronic kidney dysfunction could be more accurately evaluated ≥ 5 years after the initial treatment because patients generally finish their treatment within this period, other than those who experience recurrence or in whom secondary cancer develops. Many previous studies have identified risk factors for kidney dysfunction, including treatment with platinum-based drugs (CDDP, CBDCA, and IFO) [ 8 , 9 , 11 – 16 ], radiotherapy [ 8 , 9 , 12 , 16 ], HSCT [ 17 ], nephrectomy [ 9 , 12 – 14 , 16 ], AKI [ 17 ], and older age at the time of the initial treatment [ 8 ], and therefore these variables were considered in the present study. A summary of the findings of previous studies of the cumulative incidence of kidney dysfunction (eGFR < 90 mL/min/1.73 m 2 ) in survivors of childhood cancer is shown in Table 3 [ 8 , 9 , 13 , 14 , 18 , 19 ]. Focusing on studies limited to large numbers of patients, the cumulative incidence of kidney dysfunction has been shown to increase with time. In the present study, the cumulative incidence of kidney dysfunction was 10.7% after 5 years and 21.8% after 10 years. Mulder et al . estimated the cumulative incidence of kidney dysfunction over time, and reported that 15 years after a diagnosis, the mean probabilities of glomerular dysfunction in survivors of childhood cancer who were or were not treated with potentially nephrotoxic therapy were 5.4% and 1.7%, respectively [ 13 ], whereas the cumulative incidence of kidney dysfunction in the present study was higher. The exact reason for this disparity is unclear, but one possible explanation is that therapeutic advances have resulted in an increase in the number of survivors of severe disease that would previously have been fatal, many of whom had undergone intensive, nephrotoxic treatments. In addition, the present study included patients who visited the hospital during a specific period (from January 2021 to June 2024), and it is possible that there was a higher proportion of patients who had severe disease requiring long-term monitoring. Table 3 Prevalence of kidney dysfunction in survivors of childhood cancer (eGFR < 90 mL/min/1.73 m 2 ) n Follow-up period (median) Percentage with kidney dysfunction Arjmandi-Rafsanjani K, et al . 2008 108 35.44 months (median); 52.48 months (mean) a 24.0% Hudson MM, et al . 2013 1,713 25.6 y after diagnosis 4.5% Mulder RL, et al . 2013 1,122 21.0 y after diagnosis 5.4% 15 y after diagnosis with potentially nephrotoxic therapy 1.7% 15 y after diagnosis without potentially nephrotoxic therapy Mudi A, et al. 2016 130 2 y after treatment 17.7% Green DM, et al . 2021 2,753 23.2 y after diagnosis 18.9% Kooijmans ECM, et al . 2022 943 25.6 y after diagnosis 24.0% Present study 94 9.0 y after diagnosis 8.5% 5 y and 21.3% 10 y after diagnosis a Observation period: 35.44 months (median), 52.48 months (mean) after treatment discontinued. y years. The findings of previous studies involving multivariate analysis to identify risk factors for kidney dysfunction or CKD are summarized in Table 4 [ 8 , 9 , 13 , 14 , 16 ]. In the present study, the use of CDDP therapy, older age, and nephrectomy were the only risk factors for kidney dysfunction identified. Table 4 Risk factors for kidney dysfunction or chronic kidney disease, identified using multivariate analysis n Risk factors Mulder RL, et al. 2013 1122 ifosfamide, high doses of cisplatin, nephrectomy Mudi A, et al. 2016 130 pre-existing kidney dysfunction, ifosfamide, nephrectomy Green DM, et al . 2021 2753 older age at evaluation, grade ≥ 2 hypertension, increasing cumulative dose of ifosfamide, cisplatin, or carboplatin, treatment with a calcineurin inhibitor, volume of kidney irradiated with ≥ 5 or ≥ 10 Gy Dieffenbach BV, et al . 2021 25530 Radiotherapy dose delivered to the kidney ≥ 15 Gy, high-dose anthracycline, ifosfamide treatment, nephrectomy Kooijmans ECM, et al . 2022 1024 nephrectomy, abdominal radiotherapy, ifosfamide, cisplatin > 500 mg/m 2 Present study 94 cisplatin, older age at initial treatment, nephrectomy Platinum-based drugs, including CDDP, IFO, and CBDCA, cause damage to the proximal tubule and have long been known to be risk factors for kidney dysfunction, and the findings of the present and previous studies are consistent with this. However, the results of multivariate analysis imply that CBDCA is less frequently implicated than CDDP and IFO. Previous studies have shown that high-dose CDDP [ 13 ] and high-dose IFO [ 8 ] therapy are risk factors for kidney dysfunction. In the present study, we evaluated the effect of these factors using the log-rank test, but we identified no significant difference in the risk of kidney dysfunction between patients who were administered high or low doses. However, the absence of a significant difference with respect to CDDP might be a consequence of the limited sample size. In the present study, IFO therapy and the presence of a solid tumor were found to be significant risk factors on univariate analysis but not multivariate analysis. This was likely because CDDP therapy was a confounding factor. Of the 15 patients who underwent IFO therapy, seven developed kidney dysfunction, and five of those patients had also undergone CDDP therapy. Similarly, of the 32 patients with solid tumors, 12 developed kidney dysfunction, and 10 of these patients underwent CDDP therapy. One notable finding of the present study is that older age was a risk factor for kidney dysfunction. One previous study also showed that older age is a risk factor [ 8 ]; however, except for the studies mentioned above, the studies listed in Table 4 did not involve consideration of the age of the patients at disease onset, and therefore age at onset may also be a risk factor for kidney dysfunction. Consequently, older age should be included as a factor in future large multivariate analyses. The current study had several limitations. First, the data were collected at only one facility. Second, the sample size was relatively small. Third, the Cox proportional hazards analysis did not take into account the doses of anticancer drugs used for treatment. In conclusion, the cumulative incidence of kidney dysfunction is high (10.7% after 5 years and 21.8% after 10 years) in survivors of childhood cancer. In addition, older age (≥ 5 years) at the initiation of treatment, the use of CDDP therapy, and nephrectomy are risk factors for this condition. Therefore, long-term monitoring of kidney function is necessary for survivors of childhood cancer who have these risk factors. Declarations Conflicts of interest Koichi Nakanishi serves as a section editor of the Pediatric Nephrology journal. The authors have no other relevant financial or non-financial interests to disclose. Ethics approval The study was approved by the Ethics Committee of University of the Ryukyus (approval number: 23-2206-01-01-00) and conducted in accordance with Good Clinical Practice and the principles of the Declaration of Helsinki. Consent to participate Informed consent was obtained in the form of an opt-out on the study website. Those who elected not to participate were excluded from the study. Funding No funding was received for this study. Authors’ contributions Satoru Hamada, Hideki Sakiyama, Shinobu Kiyuna, Tokiko Oshiro, and Nobuyuki Hyakuna were the physicians who treated the patients studied. Wataru Shimabukuro conceived the study, analyzed the data, and prepared the manuscript. Satoru Hamada, Hideki Sakiyama, Shinobu Kiyuna, Tokiko Oshiro, Shogo Nakada, Kazuya Hamada, Noriko Kinjo, and Nobuyuki Hyakuna reviewed and revised the manuscript. Koichi Nakanishi conceived the study, oversaw the work, and revised the manuscript. All the authors read and approved the final version of the manuscript. Acknowledgments We thank Mark Cleasby, PhD from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this manuscript. Data availability The datasets generated during the present study will be made available by the corresponding author upon reasonable request. Code availability Not applicable. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6761059","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":462718097,"identity":"71fab7f3-1840-4150-a46e-9b2e19d602a5","order_by":0,"name":"Wataru Shimabukuro","email":"","orcid":"","institution":"Graduate School of Medhicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Wataru","middleName":"","lastName":"Shimabukuro","suffix":""},{"id":462718098,"identity":"291b14c4-b57d-4891-b38c-a0ccbeeeef4d","order_by":1,"name":"Satoru Hamada","email":"","orcid":"","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Satoru","middleName":"","lastName":"Hamada","suffix":""},{"id":462718099,"identity":"d08b2826-1ecd-4f87-afaf-592ac017eb1b","order_by":2,"name":"Hideki Sakiyama","email":"","orcid":"","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Sakiyama","suffix":""},{"id":462718100,"identity":"f228af5a-a527-476b-9698-e73899edfd70","order_by":3,"name":"Shinobu Kiyuna","email":"","orcid":"","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Shinobu","middleName":"","lastName":"Kiyuna","suffix":""},{"id":462718101,"identity":"d8af3942-2566-4355-8471-77f698faa0c7","order_by":4,"name":"Tokiko Oshiro","email":"","orcid":"","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Tokiko","middleName":"","lastName":"Oshiro","suffix":""},{"id":462718102,"identity":"dd390113-efa5-426b-bc7f-bc9099ac3239","order_by":5,"name":"Shogo Nakada","email":"","orcid":"","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Shogo","middleName":"","lastName":"Nakada","suffix":""},{"id":462718103,"identity":"8a5d1317-12cd-45e8-890b-2ef835421436","order_by":6,"name":"Kazuya Hamada","email":"","orcid":"","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Kazuya","middleName":"","lastName":"Hamada","suffix":""},{"id":462718104,"identity":"e43aa7e0-3ad8-4d74-a56f-2602c23ee2d9","order_by":7,"name":"Noriko Kinjo","email":"","orcid":"","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Noriko","middleName":"","lastName":"Kinjo","suffix":""},{"id":462718105,"identity":"92f7dea5-5141-427f-aeb3-2b1ca530d80d","order_by":8,"name":"Nobuyuki Hyakuna","email":"","orcid":"","institution":"Okinawa Red Cross Blood Center","correspondingAuthor":false,"prefix":"","firstName":"Nobuyuki","middleName":"","lastName":"Hyakuna","suffix":""},{"id":462718106,"identity":"d91c73b8-b18b-4fb8-a513-6b9a44055035","order_by":9,"name":"Koichi Nakanishi","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-8681-9129","institution":"Graduate School of Medicine, University of the Ryukyus","correspondingAuthor":true,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Nakanishi","suffix":""}],"badges":[],"createdAt":"2025-05-27 15:46:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6761059/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6761059/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-025-06972-2","type":"published","date":"2025-10-10T15:57:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83892594,"identity":"d0d8ab4d-98cd-4008-8d0f-6e3ff2ef6516","added_by":"auto","created_at":"2025-06-04 08:22:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":11102,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve describing the kidney dysfunction-free survival of the survivors of childhood cancer after their initial treatment\u003c/p\u003e","description":"","filename":"Fig111.png","url":"https://assets-eu.researchsquare.com/files/rs-6761059/v1/f8f24e91dfcc52a23ad23430.png"},{"id":83892315,"identity":"8b28a539-5675-47a6-9e1a-ea3a2666ab35","added_by":"auto","created_at":"2025-06-04 08:14:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":13910,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic curve for the prediction of kidney dysfunction using the age of patients at the time of their initial treatment. The cumulative incidence of kidney dysfunction was 10.7% after 5 years and 21.8% after 10 years\u003c/p\u003e","description":"","filename":"Fig21.png","url":"https://assets-eu.researchsquare.com/files/rs-6761059/v1/739362b2fb2cdc9c5c6f8d87.png"},{"id":83894156,"identity":"9d81a9a7-e38d-45a3-b2ba-23b5ea9ed88f","added_by":"auto","created_at":"2025-06-04 08:38:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":184619,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves describing the kidney dysfunction-free survival of patients after their initial treatment, according to various factors. a) Age at the initiation of treatment ≥5 years \u003cem\u003evs\u003c/em\u003e. \u0026lt;5 years. b) Male \u003cem\u003evs\u003c/em\u003e. female. c) Solid tumor \u003cem\u003evs\u003c/em\u003e. blood cancer. d) Cisplatin use \u003cem\u003evs\u003c/em\u003e. no use. e) Carboplatin use \u003cem\u003evs\u003c/em\u003e. no use. f) Ifosfamide use \u003cem\u003evs\u003c/em\u003e. no use. g) Nephrectomy \u003cem\u003evs\u003c/em\u003e. no nephrectomy. h) Total-body irradiation \u003cem\u003evs\u003c/em\u003e. no total-body irradiation. i) Kidney radiation dose ≥10 Gy \u003cem\u003evs\u003c/em\u003e. \u0026lt;10 Gy. j) Hematopoietic stem cell transplantation \u003cem\u003evs\u003c/em\u003e. no hematopoietic stem cell transplantation. k) Relapse or secondary cancer \u003cem\u003evs\u003c/em\u003e. no relapse or secondary cancer. l) Acute kidney injury \u003cem\u003evs\u003c/em\u003e. no acute kidney injury at the time of the initial treatment. \u003cem\u003eBC\u003c/em\u003eblood cancer, \u003cem\u003eST\u003c/em\u003e solid tumor, \u003cem\u003eCDDP \u003c/em\u003ecisplatin,\u003cem\u003e CBDCA \u003c/em\u003ecarboplatin,\u003cem\u003eIFO \u003c/em\u003eifosfamide, \u003cem\u003eNP\u003c/em\u003e nephrectomy, \u003cem\u003eTBI\u003c/em\u003e total body irradiation, \u003cem\u003eHSCT\u003c/em\u003ehematopoietic stem cell transplantation, \u003cem\u003eREL\u003c/em\u003e relapse, \u003cem\u003eSC\u003c/em\u003esecondary cancer, \u003cem\u003eAKI\u003c/em\u003e acute kidney injury.\u003c/p\u003e","description":"","filename":"Fig31.png","url":"https://assets-eu.researchsquare.com/files/rs-6761059/v1/f70a2027a78ad311043806af.png"},{"id":83892595,"identity":"6560279d-1473-43ef-a6c2-0de2b47aff95","added_by":"auto","created_at":"2025-06-04 08:22:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":38801,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve describing kidney dysfunction-free survival of the patients after their initial treatment with cisplatin and/or ifosfamide. a) Cisplatin dose ≥500 mg/m\u003csup\u003e2\u003c/sup\u003e \u003cem\u003evs\u003c/em\u003e. \u0026lt;500 mg/m\u003csup\u003e2\u003c/sup\u003e \u003cem\u003evs\u003c/em\u003e. none. b) Ifosfamide dose ≥45 g/m\u003csup\u003e2\u003c/sup\u003e \u003cem\u003evs\u003c/em\u003e. \u0026lt;45 g/m\u003csup\u003e2\u003c/sup\u003e \u003cem\u003evs\u003c/em\u003e. none. c) CDDP + IFO therapy \u003cem\u003evs\u003c/em\u003e. CDDP only \u003cem\u003evs\u003c/em\u003e. IFO only \u003cem\u003evs\u003c/em\u003e. neither. \u003cem\u003eCDDP \u003c/em\u003ecisplatin,\u003cem\u003e IFO \u003c/em\u003eifosfamide.\u003c/p\u003e","description":"","filename":"Fig41.png","url":"https://assets-eu.researchsquare.com/files/rs-6761059/v1/76fde36d8c70dce6d2b1be02.png"},{"id":93419476,"identity":"6928d2c2-febc-4157-a5a0-e4a9b3fe7148","added_by":"auto","created_at":"2025-10-13 16:02:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":971887,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6761059/v1/b97f19fd-f39b-4250-9f9f-ae59c24acdee.pdf"},{"id":83892317,"identity":"6ffdca1a-d48d-437f-8b2b-61cd3f77a056","added_by":"auto","created_at":"2025-06-04 08:14:06","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":99863,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6761059/v1/29ee84c0eed8dcbb98f299d5.pptx"},{"id":83892313,"identity":"2c0baf2d-2da9-449e-9c3c-ba5c878ac69e","added_by":"auto","created_at":"2025-06-04 08:14:06","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":40773,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-6761059/v1/1664ab5c95ebc1199726c192.docx"}],"financialInterests":"","formattedTitle":"Incidence of and risk factors for kidney dysfunction in childhood cancer survivors","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTherapeutic advances have improved the life expectancy of children with cancer. In Europe, the 5-year survival rate for such patients increased from 44% (95% CI: 44\u0026ndash;45%) in the 1970s to 77.9% (95% CI: 77.4\u0026ndash;78.3%) in 2000\u0026ndash;2007 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In Japan, the incidence of cancer-related mortality significantly decreased by 3.8% per year (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) between 1980 and 2003 for boys and 3.6% per year (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) between 1980 and 2001 for girls [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, as the life expectancy of children with cancer continues to improve, late complications affecting various organs, including the kidneys, are increasingly prevalent [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFew studies have focused on the cumulative incidence of kidney dysfunction or on the risk factors for kidney dysfunction in survivors of childhood cancer, and very few studies are aimed at identifying risk factors for kidney dysfunction using multivariate analysis. Therefore, the purpose of the present study was to measure the cumulative incidence of and identify risk factors for kidney dysfunction in survivors of childhood cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy sample\u003c/h2\u003e \u003cp\u003eWe identified 175 children with cancer who were \u0026le;\u0026thinsp;15 years old, underwent their initial treatment after 2000, visited the University of the Ryukyus Hospital between January 2021 and June 2024, and survived for \u0026gt;\u0026thinsp;5 years. Those with chromosomal or genetic abnormalities (one had 21 trisomy and another had Noonon syndrome) were excluded, as were those who did not undergo whole-body chemotherapy (six with Langerhans cell histiocytosis and four with chronic myeloid leukemia).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eThe following clinical information was collected from the medical records of the patients: age at the initiation of treatment, the length of the observation period after the initial treatment, sex, diagnosis, underlying condition, treatment details (the use of anticancer drugs, including cisplatin [CDDP], carboplatin [CBDCA], and ifosfamide [IFO]); nephrectomy; local radiation therapy; hematopoietic stem cell transplantation (HSCT); total-body irradiation (TBI) followed by HSCT; kidney radiation dose; relapse or development of secondary cancers; mortality; serum creatinine (Cr) concentration; development of acute kidney injury (AKI) during treatment; development of kidney dysfunction; introduction of continuous kidney replacement therapy; and blood pressure, serum phosphorus concentration, and proteinuria\u0026thinsp;\u0026gt;\u0026thinsp;5 years after the initial treatment.\u003c/p\u003e\n\u003ch3\u003eDefinition of kidney dysfunction\u003c/h3\u003e\n\u003cp\u003eKidney dysfunction was defined using a serum Cr-based estimated glomerular filtration rate (Cr-eGFR)\u0026thinsp;\u0026lt;\u0026thinsp;90 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e. The serum Cr concentration was measured using an enzymatic assay on a JCA-BM 6070 G (JEOL, Tokyo, Japan). Cr-eGFR was calculated using an equation based on the serum Cr concentrations of Japanese children for patients aged\u0026thinsp;\u0026le;\u0026thinsp;18 years 0 months [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and an equation based on the serum Cr concentrations of Japanese adults for patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years 1 month [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eDefinition of AKI\u003c/h3\u003e\n\u003cp\u003eA diagnosis of AKI can be made according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Acute Kidney Injury, using an increase in serum Cr of \u0026ge;\u0026thinsp;0.3 mg/dL within 48 hours, an increase in serum Cr to \u0026ge;\u0026thinsp;1.5 times the baseline value (known or presumed to have occurred within the previous 7 days), or a urine volume\u0026thinsp;\u0026lt;\u0026thinsp;0.5 mL/kg/hour for 6 hours [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, because detailed urine output data were not recorded, AKI was diagnosed purely on the basis of the serum Cr concentration in the present study.\u003c/p\u003e\n\u003ch3\u003eExposure assessment\u003c/h3\u003e\n\u003cp\u003eInformation regarding chemotherapy was obtained from the patients\u0026rsquo; medical records. The nephrotoxic agents used included CDDP, CBDCA, and IFO. For each agent, the cumulative dose (mg/m\u003csup\u003e2\u003c/sup\u003e) was calculated. Exposure to abdominal or whole-body radiation was assessed using the radiation therapy summaries, and the kidney radiation exposure was estimated by reviewing the treatment fields and calculating the radiation dose. Because doses of radiation delivered to the kidneys of \u0026ge;\u0026thinsp;10 Gy have been reported to be a risk factor for kidney dysfunction [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], the dose of radiation delivered to the kidneys was categorized as \u0026ge;\u0026thinsp;10 Gy or \u0026lt;\u0026thinsp;10 Gy. Surgical interventions involving the kidney, such as nephrectomy, were identified from the surgical records.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe cumulative incidence of kidney dysfunction was evaluated using the Kaplan\u0026ndash;Meier method. The log-rank test and Cox proportional hazards analysis were performed to evaluate the relationship between kidney dysfunction and various factors, including age at the initiation of treatment; sex; tumor type (solid or hematologic); the use of CDDP therapy, CBDCA therapy, IFO therapy, or TBI; kidney radiation dose, the use of HSCT, the occurrence of relapse or secondary cancers, and the development of AKI. Treatments administered after the onset of kidney dysfunction were not included in the multivariate analysis. In addition, a Cox proportional hazards model was used to identify risk factors for kidney dysfunction.\u003c/p\u003e \u003cp\u003eThe data generated were non-normally distributed continuous data and are expressed as median and interquartile range. \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to represent statistical significance. The data were analyzed using JMP Pro version 17.2.0 (SAS Institute Japan, Tokyo, Japan).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eData from 84 survivors, including 34 girls (40.5%), 52 with blood cancers (61.9%), and 32 with solid tumors (38.1%), were analyzed (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Supplemental Table\u0026nbsp;1). The details of the treatments are shown in Supplementary Table\u0026nbsp;2. In the entire cohort of survivors, the median (IQR) age of the patients at the initiation of treatment and the duration of the observation period were 5.7 years (1.7\u0026ndash;10.2 years) and 9.0 years (6.9\u0026ndash;11.8 years), respectively. Nineteen, 12, 15, 4, 20, 14, and 34 of the patients were treated using CDDP, CBDCA, IFO, nephrectomy, TBI followed by HSCT, a kidney radiation dose\u0026thinsp;\u0026ge;\u0026thinsp;10 Gy, and HSCT, respectively. Twelve and two of the patients relapsed or developed secondary cancer, respectively, and three died. During the treatment period, 46 of 80 patients (57.5%) developed AKI (data were not available for four patients).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatients\u0026rsquo; characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003eAll patients (n\u0026thinsp;=\u0026thinsp;84)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003eBlood cancer (n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSolid tumor (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at initial treatment, median (interquartile range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e5.7 (1.7\u0026ndash;10.2) years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e7.1 (2.8\u0026ndash;10.7) years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.3 (0.9\u0026ndash;9.1) years\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObservation period, median (interquartile range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e9.0 (6.9\u0026ndash;11.8) years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e9.1 (7.2\u0026ndash;11.8) years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.8 (6.1\u0026ndash;11.6) years\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e34(40.5%)\u003c/p\u003e\n \u003cp\u003e50(59.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e19(36.5%)\u003c/p\u003e\n \u003cp\u003e33(63.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e15(46.9%)\u003c/p\u003e\n \u003cp\u003e17(53.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eCisplatin\u003c/p\u003e\n \u003cp\u003eCarboplatin\u003c/p\u003e\n \u003cp\u003eIfosfamide\u003c/p\u003e\n \u003cp\u003eNephrectomy\u003c/p\u003e\n \u003cp\u003eTotal-body irradiation\u003c/p\u003e\n \u003cp\u003eKidney radiation dose\u0026thinsp;\u0026ge;\u0026thinsp;10 Gy\u003c/p\u003e\n \u003cp\u003eHematopoietic stem cell transplantation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e19(22.6%)\u003c/p\u003e\n \u003cp\u003e12(14.3%)\u003c/p\u003e\n \u003cp\u003e15(17.9%)\u003c/p\u003e\n \u003cp\u003e4(4.8%)\u003c/p\u003e\n \u003cp\u003e20(23.8%)\u003c/p\u003e\n \u003cp\u003e14(16.7%)\u003c/p\u003e\n \u003cp\u003e34(40.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003cp\u003e2(3.8%)\u003c/p\u003e\n \u003cp\u003e5(9.6%)\u003c/p\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003cp\u003e15(28.8%)\u003c/p\u003e\n \u003cp\u003e8(15.4%)\u003c/p\u003e\n \u003cp\u003e22(42.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e18(56.3%)\u003c/p\u003e\n \u003cp\u003e10(31.3%)\u003c/p\u003e\n \u003cp\u003e10(31.3%)\u003c/p\u003e\n \u003cp\u003e4(12.5%)\u003c/p\u003e\n \u003cp\u003e5(15.6%)\u003c/p\u003e\n \u003cp\u003e6(18.8%)\u003c/p\u003e\n \u003cp\u003e12(37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRelapse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e12(14.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e9(17.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(9.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSecondary cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e2(2.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e1(1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(3.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e3(3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e2(3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(3.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAKI during treatment \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eStage 1\u003c/p\u003e\n \u003cp\u003eStage 2\u003c/p\u003e\n \u003cp\u003eStage 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e18/80(22.5%)\u003c/p\u003e\n \u003cp\u003e18/80(22.5%)\u003c/p\u003e\n \u003cp\u003e10/80(12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e12/49(24.5%)\u003c/p\u003e\n \u003cp\u003e10/49(20.4%)\u003c/p\u003e\n \u003cp\u003e10/49(20.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e6/31(19.4%)\u003c/p\u003e\n \u003cp\u003e8/31(25.8%)\u003c/p\u003e\n \u003cp\u003e0/31(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e) at the final visit\u003c/p\u003e\n \u003cp\u003e60\u0026ndash;89\u003c/p\u003e\n \u003cp\u003e30\u0026ndash;59\u003c/p\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e16(19.0%)\u003c/p\u003e\n \u003cp\u003e4(4.8%)\u003c/p\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e8(15.4%)\u003c/p\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e8(25.0%)\u003c/p\u003e\n \u003cp\u003e4(12.5%)\u003c/p\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eContinuous kidney replacement therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertension at the final measurement \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e9/81(11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e6/51(11.88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3/30(10.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypophosphatemia at the final examination \u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e11/74(14.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e5/47(10.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/27(22.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProteinuria at the final examination \u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.4316%;\"\u003e\n \u003cp\u003e3/75(4.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 21.1511%;\"\u003e\n \u003cp\u003e0/46(0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3/29(10.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Excluding treatment after the onset of kidney dysfunction. \u003csup\u003eb\u003c/sup\u003e Four patients had not received an initial treatment at our hospital and no laboratory data were available. \u003csup\u003ec\u003c/sup\u003e Patients who did not have their blood pressure, serum phosphorus concentration, or urine analyzed once \u0026ge;\u0026thinsp;5 years after their initial treatment were excluded. \u003cem\u003eAKI\u003c/em\u003e acute kidney injury, \u003cem\u003eeGFR\u003c/em\u003e estimated glomerular filtration rate.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eKidney dysfunction was diagnosed in 20 of the patients (23.8%) at their last visits, and there were 5-year and 10-year cumulative incidences of 10.7% and 21.8%, respectively, according to the Kaplan\u0026ndash;Meier curve (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). None of the patients initiated continuous kidney replacement therapy during the study. The patients were divided into older and younger age groups at the initiation of treatment using a threshold of 5 years, based on ROC analysis (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe log-rank test identified risk factors for kidney dysfunction of older age (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), the presence of a solid tumor (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), the use of CDDP therapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), the use of IFO therapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and nephrectomy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Subgroup analyses were then performed with respect to CDDP and IFO therapy, with the patients being divided into dosage-based groups (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e) [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. Log-rank analysis of the use of CDDP therapy using three groups (\u0026ge;\u0026thinsp;500 mg/m\u003csup\u003e2\u003c/sup\u003e, \u0026lt;\u0026thinsp;500 mg/m\u003csup\u003e2\u003c/sup\u003e, and none) showed no significant difference between the \u0026ge;\u0026thinsp;500 mg/m\u003csup\u003e2\u003c/sup\u003e and \u0026lt;\u0026thinsp;500 mg/m\u003csup\u003e2\u003c/sup\u003e groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.069); and log-rank analysis of the use of IFO therapy using three groups (\u0026ge;\u0026thinsp;45 g/m\u003csup\u003e2\u003c/sup\u003e, \u0026lt;\u0026thinsp;45 g/m\u003csup\u003e2\u003c/sup\u003e, and none) showed no significant difference between the \u0026ge;\u0026thinsp;45 g/m\u003csup\u003e2\u003c/sup\u003e and \u0026lt;\u0026thinsp;45 g/m\u003csup\u003e2\u003c/sup\u003e groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.854). In addition, log-rank analysis of four groups of patients (CDDP\u0026thinsp;+\u0026thinsp;IFO therapy, CDDP therapy only, IFO therapy only, and none) showed no significant difference between the CDDP therapy only and CDDP\u0026thinsp;+\u0026thinsp;IFO therapy groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.061).\u003c/p\u003e\n\u003cp\u003eCox proportional hazards analysis was then performed. Univariate analysis showed that older age (HR 4.04, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013), the presence of a solid tumor (HR 3.39, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), the use of CDDP therapy (HR 5.84, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), the use of IFO therapy (HR 4.31, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), and nephrectomy (HR 4.55, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046) were risk factors for kidney dysfunction. Multivariate analysis that included these five factors showed that older age (HR 3.89, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033), the use of CDDP therapy (HR 8.80, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and nephrectomy (HR 10.20, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) were significant risk factors (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eResults of the Cox proportional hazards analyses to identify factors influencing the development of kidney dysfunction\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at initial treatment\u0026thinsp;\u0026ge;\u0026thinsp;5 years (\u003cem\u003evs\u003c/em\u003e. \u0026lt; 5 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.35\u0026ndash;12.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.12\u0026ndash;13.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale (\u003cem\u003evs\u003c/em\u003e. female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.68\u0026ndash;4.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.245\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSolid tumor (\u003cem\u003evs\u003c/em\u003e. blood cancer)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.38\u0026ndash;8.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.24\u0026ndash;2.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.752\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDDP (\u003cem\u003evs\u003c/em\u003e. no use)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.41\u0026ndash;14.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.51\u0026ndash;30.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCBDCA (\u003cem\u003evs\u003c/em\u003e. no use)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.39\u0026ndash;4.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.639\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIFO (\u003cem\u003evs\u003c/em\u003e. no use)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.63\u0026ndash;11.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69\u0026ndash;7.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.178\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNephrectomy (\u003cem\u003evs\u003c/em\u003e. no nephrectomy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.03\u0026ndash;20.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.046\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.56\u0026ndash;66.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTBI (\u003cem\u003evs\u003c/em\u003e. no TBI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.45\u0026ndash;3.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.745\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKidney radiation dose\u0026thinsp;\u0026ge;\u0026thinsp;10 Gy (\u003cem\u003evs\u003c/em\u003e. \u0026lt;10 Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.52\u0026ndash;3.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.480\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHSCT (\u003cem\u003evs\u003c/em\u003e. no HSCT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.71\u0026ndash;4.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.223\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRelapse/SC (\u003cem\u003evs\u003c/em\u003e. no Relapse/SC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.38\u0026ndash;3.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.834\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAKI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.50\u0026ndash;3.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003e\u003cem\u003eHR\u003c/em\u003e hazard ratio, \u003cem\u003eCDDP\u003c/em\u003e cisplatin, \u003cem\u003eCBDCA\u003c/em\u003e carboplatin, \u003cem\u003eIFO\u003c/em\u003e ifosfamide, \u003cem\u003eTBI\u003c/em\u003e total-body irradiation, \u003cem\u003eHSCT\u003c/em\u003e hematopoietic stem cell transplantation, \u003cem\u003eSC\u003c/em\u003e secondary cancer, \u003cem\u003eAKI\u003c/em\u003e acute kidney injury.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we analyzed a cohort of survivors of childhood cancer whose kidney function was monitored for the \u0026ge;\u0026thinsp;5 years following their initial treatment. When kidney function is evaluated during treatment, it is important to consider the effects of AKI and that the Cr-eGFR can be overestimated in the presence of muscle weakness. Therefore, we considered that chronic kidney dysfunction could be more accurately evaluated\u0026thinsp;\u0026ge;\u0026thinsp;5 years after the initial treatment because patients generally finish their treatment within this period, other than those who experience recurrence or in whom secondary cancer develops. Many previous studies have identified risk factors for kidney dysfunction, including treatment with platinum-based drugs (CDDP, CBDCA, and IFO) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], radiotherapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], HSCT [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], nephrectomy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], AKI [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and older age at the time of the initial treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and therefore these variables were considered in the present study.\u003c/p\u003e \u003cp\u003eA summary of the findings of previous studies of the cumulative incidence of kidney dysfunction (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e) in survivors of childhood cancer is shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Focusing on studies limited to large numbers of patients, the cumulative incidence of kidney dysfunction has been shown to increase with time. In the present study, the cumulative incidence of kidney dysfunction was 10.7% after 5 years and 21.8% after 10 years. Mulder \u003cem\u003eet al\u003c/em\u003e. estimated the cumulative incidence of kidney dysfunction over time, and reported that 15 years after a diagnosis, the mean probabilities of glomerular dysfunction in survivors of childhood cancer who were or were not treated with potentially nephrotoxic therapy were 5.4% and 1.7%, respectively [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], whereas the cumulative incidence of kidney dysfunction in the present study was higher. The exact reason for this disparity is unclear, but one possible explanation is that therapeutic advances have resulted in an increase in the number of survivors of severe disease that would previously have been fatal, many of whom had undergone intensive, nephrotoxic treatments. In addition, the present study included patients who visited the hospital during a specific period (from January 2021 to June 2024), and it is possible that there was a higher proportion of patients who had severe disease requiring long-term monitoring.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrevalence of kidney dysfunction in survivors of childhood cancer (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFollow-up period (median)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePercentage with kidney dysfunction\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArjmandi-Rafsanjani K, \u003cem\u003eet al\u003c/em\u003e. 2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.44 months (median);\u003c/p\u003e \u003cp\u003e52.48 months (mean)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHudson MM, \u003cem\u003eet al\u003c/em\u003e. 2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1,713\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.6 y after diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMulder RL, \u003cem\u003eet al\u003c/em\u003e. 2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1,122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.0 y after diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.4% 15 y after diagnosis with potentially nephrotoxic therapy\u003c/p\u003e \u003cp\u003e1.7% 15 y after diagnosis without potentially nephrotoxic therapy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMudi A, \u003cem\u003eet al.\u003c/em\u003e 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 y after treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGreen DM, \u003cem\u003eet al\u003c/em\u003e. 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2,753\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.2 y after diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKooijmans ECM, \u003cem\u003eet al\u003c/em\u003e. 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e943\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.6 y after diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0 y after diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.5% 5 y and 21.3% 10 y after diagnosis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e Observation period: 35.44 months (median), 52.48 months (mean) after treatment discontinued. \u003cem\u003ey\u003c/em\u003e years.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe findings of previous studies involving multivariate analysis to identify risk factors for kidney dysfunction or CKD are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the present study, the use of CDDP therapy, older age, and nephrectomy were the only risk factors for kidney dysfunction identified.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors for kidney dysfunction or chronic kidney disease, identified using multivariate analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRisk factors\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMulder RL, \u003cem\u003eet al.\u003c/em\u003e 2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eifosfamide, high doses of cisplatin, nephrectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMudi A, \u003cem\u003eet al.\u003c/em\u003e 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003epre-existing kidney dysfunction, ifosfamide, nephrectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGreen DM, \u003cem\u003eet al\u003c/em\u003e. 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2753\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eolder age at evaluation, grade\u0026thinsp;\u0026ge;\u0026thinsp;2 hypertension, increasing cumulative dose of ifosfamide, cisplatin, or carboplatin, treatment with a calcineurin inhibitor, volume of kidney irradiated with \u0026ge;\u0026thinsp;5 or \u0026ge;\u0026thinsp;10 Gy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDieffenbach BV, \u003cem\u003eet al\u003c/em\u003e. 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25530\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRadiotherapy dose delivered to the kidney\u0026thinsp;\u0026ge;\u0026thinsp;15 Gy, high-dose anthracycline, ifosfamide treatment, nephrectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKooijmans ECM, \u003cem\u003eet al\u003c/em\u003e. 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003enephrectomy, abdominal radiotherapy, ifosfamide, cisplatin\u0026thinsp;\u0026gt;\u0026thinsp;500 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ecisplatin, older age at initial treatment, nephrectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePlatinum-based drugs, including CDDP, IFO, and CBDCA, cause damage to the proximal tubule and have long been known to be risk factors for kidney dysfunction, and the findings of the present and previous studies are consistent with this. However, the results of multivariate analysis imply that CBDCA is less frequently implicated than CDDP and IFO. Previous studies have shown that high-dose CDDP [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and high-dose IFO [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] therapy are risk factors for kidney dysfunction. In the present study, we evaluated the effect of these factors using the log-rank test, but we identified no significant difference in the risk of kidney dysfunction between patients who were administered high or low doses. However, the absence of a significant difference with respect to CDDP might be a consequence of the limited sample size.\u003c/p\u003e \u003cp\u003eIn the present study, IFO therapy and the presence of a solid tumor were found to be significant risk factors on univariate analysis but not multivariate analysis. This was likely because CDDP therapy was a confounding factor. Of the 15 patients who underwent IFO therapy, seven developed kidney dysfunction, and five of those patients had also undergone CDDP therapy. Similarly, of the 32 patients with solid tumors, 12 developed kidney dysfunction, and 10 of these patients underwent CDDP therapy.\u003c/p\u003e \u003cp\u003eOne notable finding of the present study is that older age was a risk factor for kidney dysfunction. One previous study also showed that older age is a risk factor [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; however, except for the studies mentioned above, the studies listed in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e did not involve consideration of the age of the patients at disease onset, and therefore age at onset may also be a risk factor for kidney dysfunction. Consequently, older age should be included as a factor in future large multivariate analyses.\u003c/p\u003e \u003cp\u003eThe current study had several limitations. First, the data were collected at only one facility. Second, the sample size was relatively small. Third, the Cox proportional hazards analysis did not take into account the doses of anticancer drugs used for treatment.\u003c/p\u003e \u003cp\u003eIn conclusion, the cumulative incidence of kidney dysfunction is high (10.7% after 5 years and 21.8% after 10 years) in survivors of childhood cancer. In addition, older age (\u0026ge;\u0026thinsp;5 years) at the initiation of treatment, the use of CDDP therapy, and nephrectomy are risk factors for this condition. Therefore, long-term monitoring of kidney function is necessary for survivors of childhood cancer who have these risk factors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of interest\u003c/h2\u003e \u003cp\u003eKoichi Nakanishi serves as a section editor of the Pediatric Nephrology journal. The authors have no other relevant financial or non-financial interests to disclose.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003e The study was approved by the Ethics Committee of University of the Ryukyus (approval number: 23-2206-01-01-00) and conducted in accordance with Good Clinical Practice and the principles of the Declaration of Helsinki.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003e Informed consent was obtained in the form of an opt-out on the study website. Those who elected not to participate were excluded from the study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding was received for this study.\u003c/p\u003e\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e \u003cp\u003eSatoru Hamada, Hideki Sakiyama, Shinobu Kiyuna, Tokiko Oshiro, and Nobuyuki Hyakuna were the physicians who treated the patients studied. Wataru Shimabukuro conceived the study, analyzed the data, and prepared the manuscript. Satoru Hamada, Hideki Sakiyama, Shinobu Kiyuna, Tokiko Oshiro, Shogo Nakada, Kazuya Hamada, Noriko Kinjo, and Nobuyuki Hyakuna reviewed and revised the manuscript. Koichi Nakanishi conceived the study, oversaw the work, and revised the manuscript. All the authors read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eWe thank Mark Cleasby, PhD from Edanz (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jp.edanz.com/ac\u003c/span\u003e\u003cspan address=\"https://jp.edanz.com/ac\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) for editing a draft of this manuscript.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eThe datasets generated during the present study will be made available by the corresponding author upon reasonable request.\u003c/p\u003e\u003ch2\u003eCode availability\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSteliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh JW, Lacour B, Parkin M (2004) Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCIS project): an epidemiological study. 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JAMA 309:2371\u0026ndash;2381. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jama.2013.6296\u003c/span\u003e\u003cspan address=\"10.1001/jama.2013.6296\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Childhood cancer survivor, Kidney dysfunction, Late complication, Chronic kidney disease","lastPublishedDoi":"10.21203/rs.3.rs-6761059/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6761059/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlthough therapeutic advances have improved the life expectancy of children with cancer, the late complication of kidney dysfunction represents a challenge. We aimed to measure the cumulative incidence and identify risk factors for kidney dysfunction (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;90 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e) in survivors of childhood cancer.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe studied children treated for cancer who survived for \u0026gt;\u0026thinsp;5 years. The cumulative incidence of kidney dysfunction was measured and risk factors were identified using the Kaplan\u0026ndash;Meier method, the log-rank test, and Cox proportional hazards analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eEighty-four survivors, who were a median of 5.7 years old at the start of treatment, were studied for a median of 9.0 years. Nineteen, 12, 15, 4, 20, 14, and 34 patients were treated using cisplatin (CDDP), carboplatin, ifosfamide, nephrectomy, total-body irradiation, kidney irradiation (\u0026ge;\u0026thinsp;10 Gy), or hematopoietic stem cell transplantation, respectively; and 14 developed relapse/secondary cancer. During treatment, acute kidney injury developed in 57.5% of patients. The cumulative incidence of kidney dysfunction was 10.7% after 5 years and 21.8% after 10 years. The log-rank test identified older age (\u0026ge;\u0026thinsp;5 years) at the initiation of treatment, solid tumor, CDDP therapy, ifosfamide therapy, and nephrectomy as significant risk factors; and a Cox proportional hazards model showed that older age (HR 3.89, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033), CDDP therapy (HR 8.80, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and nephrectomy (HR 10.20, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) were significant risk factors.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe long-term monitoring of kidney function is important for survivors of childhood cancer who received their initial treatment when relatively old, underwent CDDP-based chemotherapy, or underwent nephrectomy.\u003c/p\u003e","manuscriptTitle":"Incidence of and risk factors for kidney dysfunction in childhood cancer survivors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-04 08:14:01","doi":"10.21203/rs.3.rs-6761059/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2025-06-06T17:13:46+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-05-27T21:01:35+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-27T20:42:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-27T18:36:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2025-05-27T11:42:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6f8255a3-f89b-4ac8-9ac6-32d09cc50fce","owner":[],"postedDate":"June 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T15:59:04+00:00","versionOfRecord":{"articleIdentity":"rs-6761059","link":"https://doi.org/10.1007/s00467-025-06972-2","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2025-10-10 15:57:00","publishedOnDateReadable":"October 10th, 2025"},"versionCreatedAt":"2025-06-04 08:14:01","video":"","vorDoi":"10.1007/s00467-025-06972-2","vorDoiUrl":"https://doi.org/10.1007/s00467-025-06972-2","workflowStages":[]},"version":"v1","identity":"rs-6761059","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6761059","identity":"rs-6761059","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}